Pulmonary hypertension (PH) in children or adults is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Although the number of vasodilator drugs has increased, still 20-30% of patients do not respond and non-responders have a poor prognosis eventually requiring lung transplantation1-4. Pulmonary hypertension is frequently identified in patients with Down syndrome and is associated with increased mortality, especially in patients with congenital heart disease (CHD).5-8 In the University of Colorado Down syndrome clinic, 27.6% of patients had pulmonary hypertension.9 Although pulmonary hypertension increases morbidity and mortality in subjects with Down syndrome, the underlying disease burden and the role of specific comorbidities that increase the risk of developing pulmonary hypertension in Down syndrome are not completely understood.9 A major reason, is we lack simple, minimally invasive more lung/vascular specific, objective, repeatable, generalizable and less expensive measures of PH in Down syndrome to improve outcomes. The study, ?Clinical and mechanistic role of HDGF in pulmonary hypertension? R01HL135114-02 awarded from the National Heart Lung and Blood Institute, aims to elucidate the in vitro and in vivo mechanistic role of HDGF in Group I pulmonary artery hypertension and potential as a circulating new measure of PAH severity, therapeutic response and survival. With the parent study we have established collaborations with the NHLBI PAHBiobank at the University of Cinicinnati, Vanderbilt University and Denver Children?s at the University of Colorado, and have assayed >2100 samples from children and adults with pulmonary arterial hypertension (PAH, WHO Group I) and normal adult and pediatric controls, using custom built multiplex ELISAs for hepatoma derived growth factor (HDGF) a pulmonary angiogenic protein that is significantly associated with PH survival and functional outcomes (6 minute walk distance),10 and historical PH biomarkers as benchmarks including the standard clinical heart failure biomarkers (NTproBNP, ST2, GAL3), inflammation (IL6), and angiogenesis (VEGF and endostatin). Endostatin is particularly important as it is an angiogenic inhibitor fragment of collagen 18A, and significantly associated with survival and functional outcomes in patients with PH and located on Chromosome 21.11 Despite the success of the parent study, it is focused only on WHO Group I pulmonary arterial hypertension and did not include patients with Down syndrome. Therefore, considering the incidence of PH in Down syndrome and the paucity of biomarker studies, there is an urgent need to identify PH diagnostic/prognostic biomarkers to improve outcomes in Down syndrome. Overarching objective: To augment the ?Clinical and mechanistic role of HDGF in pulmonary hypertension? study using the INCLUDE research objective of Component 2 to add a new Down Syndrome cohort for circulating PH biomarker analysis with and without PH and comparison to a large WHO Group I cohort (N=2100) and normal adults (N=110) and children (N=165).